RS52548B - Oral dosage form containing a pde 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient - Google Patents

Abstract

An oral tablet dosage form comprising a PDE 4 inhibitor together with polyvinylpyrrolidone, and one or more suitable pharmaceutical excipients, wherein the PDE 4 inhibitor is a compound selected from the group of compounds of formula I wherein R 1 is difluoromethoxy, R 2 is cyclopropylmethoxy, and R 3 is 3,5-dichloropyrid-4-yl, as well as salts of this compound, and N-oxide of pyridine and its salts, and wherein the dosage form does not contain a PDE 4 inhibitor evenly dispersed or dissolved in an excipient matrix composed of one or more excipients selected from groups of fatty alcohols, triglycerides, partial glyceride and fatty acid ester. The application contains 4 more independent and 42 dependent patent claims.

Description

Technical field

This invention relates to the field of pharmaceutical technology and describes a dosage form for oral administration of a PDE 4 inhibitor as an active ingredient in tablet or granule form for the treatment of diseases such as asthma or respiratory disorders. The invention additionally relates to procedures for obtaining a dosage form.

State of the art

Cyclic nucleotide phosphodiesterase (PDE) inhibitors (especially type 4) are current and of particular interest as a new generation of active ingredients for the treatment of inflammatory diseases, especially airway inflammation such as asthma or airway inflammation (such as, for example, COPD = chronic obstructive pulmonary disease). A number of PDE 4 inhibitors are currently undergoing advanced clinical trials.

In WO 00/50011 and WO 01/32165, which relate to controlled or sustained release dosage forms of PDE 4 inhibitors, it has been pointed out that adverse CNS effects may occur in relation to release in a certain degree of PDE 4 inhibitors such as Ariflo<®> (INN: cilomilast) in higher dosage. WO 00/50011 and WO 01/32165 state that there is a particular risk due to the immediate release of the active ingredient from the dosage form and therefore suggest taking the PDE 4 inhibitor Ariflo<®> (INN: cilomilast) in controlled or sustained release dosage forms. Another immediate release dosage form of cilomilast is described in WO 01/60358.

US Patent 5,286,494 proposes controlled or sustained release dosage forms of the low solubility PDE 4 inhibitor Rolipram. However, the production of dosage forms with controlled or sustained release of a sparingly soluble active ingredient can be technically complicated, and reference to this is given in the example of US patent 5,286,494.

The solubility of the active ingredient of the PDE 4 inhibitor class in water and aqueous systems may, depending on the chemical structure, be low. Thus, the water solubility found for the PDE 4 inhibitor N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenz-amide (INN: roflumilast), which is described in WO95/01338, is only 0.53 mg/l at 21 °C. The bioavailability of the medicinal substance depends essentially on the release of the medicinal substance from the pharmaceutical form. Fast release and dissolution of the medicinal substance from the formulation means its faster absorption. For medicinal substances that are less soluble in water, therefore, bioavailability is limited by their solubility or dissolution rate. This creates great difficulties for the production of suitable dosage forms. WO 02/45693 which represents the state of the art under Article 54(3) EPC, describes the preparation where the active ingredient, primarily roflumilast, its N-oxide or its pharmacologically suitable salt, is uniformly dispersed or dissolved in an excipient matrix which is composed of one or more excipients selected from the group of fatty alcohol, triglyceride, partial glyceride and fatty acid ester.

Description of the invention

The object of the present invention is to provide a dosage form for oral administration of a PDE 4 inhibitor with a low solubility, which forms can be produced without great technical requirements, which relate to a low solubility of a PDE 4 inhibitor, whose solubility is low, and which results in a faster, acceptable bioavailability of a PDE 4 inhibitor, whose solubility is low, so that the level of the active substance that is needed in order to achieve the desired pharmaceutical effect faster without side effects that can be report, bigger.

It has now been found that this can be achieved with an oral dosage form of a PDE 4 inhibitor, which has low solubility, using polyvinylpyrrolidine (PVP) as a filler in the dosage form. Compared with dosage forms in which no PVP is used as a filler, the dosage form of this invention shows a visible improvement in pharmacokinetic properties. Thus, in terms of the bioavailability ratio of the PDE 4 inhibitor, whose solubility is low, a faster absorption and thus a faster onset of the pharmacological effect is obtained with the dosage form of the present invention compared to the dosage form without PVP. The oral dosage form of the invention is preferably in a solid dosage form such as a tablet or granule form. A solid dosage form with immediate release of the active ingredient (immediate release from a solid oral dosage form) is preferred.

The invention thus relates to a dosage form in the form of a tablet or granule for oral administration of a PDE 4 inhibitor, the solubility of which is low, compared to a PDE 4 inhibitor, the solubility of which is low, together with polyvinylpyrrolidone as a filler and one or more other suitable pharmaceutical components.

PDE 4 inhibitor, whose solubility is low, is preferably according to the invention a compound from the group of compounds of formula I

in which one or the other

R1 is difluoromethoxy,

R2 is cyclopropylmethoxy and,

R3 is 3,5-dichloropyrid-4-yl,

as well as salts of this compound and N-oxide of pyridine and its salts, and

wherein the dosage form does not contain a PDE 4 inhibitor uniformly dispersed or dissolved in an excipient matrix composed of one or more excipients selected from the group of fatty alcohol, triglyceride, partial glyceride, and fatty acid ester.

This compound has the chemical name N-(3,5-dichloropyrid-4-yl)-3-cyclopropyl-methoxy-4-difluoromethoxy-benzamide (INN: roflumilast).

Salts suitable for the compounds of formula I - depending on the substitution - are all acid addition salts but, in particular, all salts with bases. In particular, the said compound can be obtained from pharmaceutically acceptable salts of inorganic and organic acids and bases that are commonly used in pharmaceutical technology. Pharmacologically unacceptable salts, which, for example, can be starting products for the process of obtaining the compounds of the invention on an industrial scale, are translated into pharmaceutically acceptable salts by methods known in the art. These suitable salts are on the one hand water-soluble and water-insoluble acid addition salts such as, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxy-benzoyl)benzoic acid, sulfosalicylic acid, maleic acid, lauric acid, formic acid, succinic acid, oxalic acid, tartaric acid, embolic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, are acids that are used to obtain salts in an equimolar ratio of their quantities or as a difference in relation to their form - depending on whether the acid is monobasic or polybasic and depending on which salt is to be obtained.

On the other hand, salts with bases are also preferably suitable. Examples of base salts that can be cited are lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, and again, depending on which salt is obtained, they are used in an equimolar ratio or a multimolar ratio depending on their form.

A PDE 4 inhibitor having a low solubility is preferably a PDE 4 inhibitor with a water solubility of less than or equal to 100 milligrams/liter, particularly preferably with a water solubility of less than or equal to 1 milligram/liter at a temperature of 15 to 25°C, especially at 21°C. Such a compound is particularly preferred for formula I.

The aforementioned compounds of formula I and the use of these compounds as phosphodiesterase (PDE) 4 inhibitors are described in International Patent Application WO95/01338.

Further, suitable pharmaceutical excipients that may be used in the dosage forms of the present invention are pharmaceutical excipients such as fillers, additional binders, tablet disintegrants or other lubricants and release agents. Other suitable excipients that may be present in the dosage form of the present invention are, for example, flavoring agents (such as flavoring agents or sweeteners), buffering agents, preservatives, coloring agents (such as iron oxide yellow or red) or other emulsifiers. Flavors are usually added at 0.05 to 1% of the total weight. Other flavoring substances are, for example, acids such as citric acid, sweeteners such as saccharin, aspartame, sodium cyclamate or maltol, which are added in amounts to achieve the desired effect.

The polyvinylpyrrolidone (PVP) used according to the invention is, in particular, a water-soluble PVP with an average molecular weight above 2,000, preferably above 20,000. Examples that can be cited are Kolidon 12 PF (molecular weight 2,000-3,000), Kolidon 17 PF (molecular weight 7,000-11,000), Kolidon 25 (molecular weight 28 000 - 34 000), Kolydon 30 (molecular weight 44 000 - 54 000), Kolydon 90 F (molecular weight 1 000 000 - 1 500 000). PVPs of higher molecular weights, such as, for example, Kolydon 25, Kolydon 30 and Kolydon 90 F may be preferred.

It is possible, if desired, to use other PVP binders such as polyvinyl acetate (for example Kolydon<®>VA 64), gelatin, gummy corn starch, pressed wool starch (starch 1500), hydroxypropylmethyl cellulose (HPMC) or hydroxypropyl cellulose.

(L-HPC).

Suitable fillers according to the present invention are carriers such as calcium carbonate (for example MagGran® CC or Destab<®>95) and sodium carbonate, sugar alcohols such as mannitol (for example Perlitol<®> or Parteck<®>M), sorbitol (for example Karion<®>), xylitol or allitol, starches such as corn starch, calum starch and wheat starch, microcrystalline cellulose, saccharides such as glucose, lactose (on eg lactose monohydrate), levulose, sucrose and dextrose. It is also possible, if desired, to use their mixture. Corn starch, monocrystalline cellulose and lactose may be mentioned as preferred.

Examples of suitable lubricants and release agents which may be mentioned are sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid, talc and colloidal anhydrous silica (Aerosil).

Disintegrants suitable according to this invention are, in particular, insoluble polyvinylpyrrolidone (insoluble PVP, crospovdone), sodium carboxymethyl starch [=sodium starch glycolate], sodium carboxymethyl cellulose, alginic acid and starch capable of providing a tablet disintegrating function (for example, starch 1500).

Proportionally (in percent by weight of the final dosage form) PDE 4 inhibitor in a dosage form of the present invention is usually, depending on the nature of the PDE 4 inhibitor, from 0.01 to 50% by weight. The proportion of PDE 4 inhibitor is preferably up to 20% by weight.

The proportional (percentage by weight of the final dosage form) binder (PVP and, where appropriate, other binders) may preferably be from 0.5 to 20% by weight according to the present invention.

The proportion of PVP is preferably from 1 to 5% by weight, particularly preferably from 2 to 3% by weight.

Proportionately (in percent by weight of the final dosage form) the fillers in the tablets of the present invention are advantageously from 40 to 99% by weight. Proportionally, the filler should preferably be from 60 to 97% by weight.

Proportionately (as a percentage by weight of the final dosage form) disintegrants in a rapidly disintegrating tablet can typically be up to 35% by weight. Proportionally, disintegrants are preferably from 2 to 20% by weight. Proportional disintegrants are particularly preferred to be 5 to 10% by weight.

In a preferred embodiment of the present invention, the dosage form is a tablet. It is desirable that the tablet, in addition to the PDE 4 inhibitor, whose solubility is low, and the PVP include as a further use pharmaceutical acceptors of at least one filler and of at least one lubricant or release agent.

The pharmaceutical production of the invention can be carried out using methods known in the art for the production of tablets and granules.

In one improvement of this invention, the pharmaceutical form of the invention is obtained by making a solid solution of a PDE 4 inhibitor, which has a low solubility, in a PVP binder as a carrier. This may be an example of a dissolution process in which the PVP, PDE 4 inhibitor and, where appropriate, other pharmaceutical excipients are dissolved in a suitable solvent and then the solvent is removed using spray drying, normal drying, vacuum drying or freeze drying methods. It has been found, unexpectedly, that the production of a solid solution is also possible using a mixing process in which the PDE 4 inhibitor, which has a low solubility, and, where possible, other pharmaceutical acceptors are vigorously mixed together with the PVP.

The invention also further relates to a solid solution of a PDE 4 inhibitor, the solubility of which is low, in a PVP filler as a carrier. A solid solution of a PDE 4 inhibitor in a PVP filler as a carrier means according to the invention a solid solution with an amorphous structure in which the PDE 4 inhibitor is in the form of a molecular dispersion in the carrier material.

In the case of further making the solid solution into tablets or granules, the solid solution can be made as a component of the active ingredient along with components such as filler, binder, disintegrant and lubricant by methods known to manufacturers for obtaining an oral dosage form of this invention.

The invention therefore also relates to the procedure for the production of a dosage form

tablets or granules for oral administration with a PDE 4 inhibitor and which includes the steps: (a) production of the active ingredient in the form of a solid solution in PVP with a PDE 4 inhibitor, the solubility of which is low, (b) production of a mixture of active ingredients and pharmaceutical excipients and (c) granulation of the obtained mixture in (b) with an aqueous solution of PVP.

In case the dosage form of the present invention is in tablet form, the granules obtained in (c) may, after drying and mixing with a lubricant or release agent, be compressed into tablets using a tablet press. In the event that the dosage form of the present invention is in the form of balls, the wet granules obtained in (c) may be converted into corresponding balls by means of an extrusion/spheroid process. Alternatively, dispersions/suspensions of the active ingredient can be obtained by applying a solid solution form in PVP with a PDE 4 inhibitor, the solubility of which is low, in a suitable solvent as a carrier for the granules (eg nonpareils or HPMC - containing spheres).

In a further preferred development of this invention, the dosage form of the invention is obtained by granulating a mixture of active ingredients and pharmaceutical excipients with an aqueous PVP solution, drying the granules and, if desired, re-mixing with other pharmaceutical excipients. The wet process of obtaining, after granulation, can then be a further process of production into balls and can then be packed into capsules. Dried granules can, if desired, after re-mixing with other pharmaceutical acceptors - after mixing with a releasing agent, be pressed into tablets using a press. Granulation is preferably carried out in a fluidized bed in a granulator under suitable conditions. Also, it is possible, if desired, for the active ingredients to be re-mixed with other pharmaceutical excipients in the desired form with pharmaceutical acceptors (especially fillers). This is particularly desirable when the active ingredient is contained in the dosage form in an amount of less than 5% by weight. This comminution can normally be accomplished by comminuting the active ingredient with pharmaceutical excipients (especially a filler).

The invention also relates to a process for producing a dosage form in a form

tablets or granules for oral administration of PDE 4 inhibitors and includes the following steps:

(a) producing a mixture of the active ingredient and pharmaceutical excipients and (b) granulating the mixture obtained in (a) with an aqueous solution of PVP. The dosage form of the present invention is particularly preferred for the production of granules of a mixture of (a) PDE 4 inhibitors, the solubility of which is low, or by crushing the PDE 4 inhibitor,

whose solubility is low, with corn starch,

(b) corn starch and

(c) lactose monohydrate

with an aqueous PVP solution, drying the granules, mixing the granules with a release agent and pressing them into tablets in a tablet press. A PDE 4 inhibitor, the solubility of which is low, in this case roflumilast, as well as its salts, N-oxide pyridine and its salts, are particularly preferred.

Alternatively, the dosage form of the present invention is particularly preferably obtained by granulating a mixture of (a) a PDE 4 inhibitor, the solubility of which is low, or by crushing the PDE 4 inhibitor,

whose solubility is low, with corn starch,

(b) corn starch,

(c) microcrystalline cellulose and

(d) sodium carboxymethyl starch

with an aqueous PVP solution, drying the granules, mixing the granules with a release agent and pressing them into tablets in a tablet press. A PDE 4 inhibitor, the solubility of which is low, in this case particularly preferably roflumilast, as well as its salts, N-oxide of pyridine and its salts.

In a further preferred development of this invention, the dosage form in the invention is obtained by granulating a mixture of pharmaceutical excipients with a suspension of active ingredients in an aqueous PVP solution, drying the obtained granules and, if desired, re-mixing with further pharmaceutical excipients. The mixture obtained in this way is then, after mixing with the release agent, pressed into tablets in a tablet press. Granulation is preferably carried out in a fluidized bed under suitable conditions.

The invention thus also relates to a process for the production of a dosage form in the form of a tablet or granule for oral intake of a PDE 4 inhibitor, which includes the steps:

(a) production of a mixture of pharmaceutical acceptors and

(b) granulating the mixture obtained in (a) with a suspension of the active ingredients in an aqueous solution of PVP.

The dosage form in this invention is particularly preferably produced by granulating a mixture of corn starch and lactose monohydrate with a suspension of PDE 4 inhibitors, the solubility of which is low, in a suitable aqueous solution of PVP, drying and granulating, mixing the granules with a releasing agent and pressing them into tablets in

tablet press.

It has surprisingly been found that a dosage form of the present invention obtained by using a physical mixture or by comminuting a low solubility PDE 4 inhibitor with fillers (for example by grinding, live mixing or extrusion) and then granulating in an aqueous PVP solution or using a granulated suspension process of a PDE 4 inhibitor in an aqueous PVP solution has similar advantages in properties, in terms of the bioavailability of a low solubility PDE 4 inhibitor, as dosage forms obtained from a solid solution of PVP and PDE 4 inhibitors. This indicates that in the production of the dosage forms of the present invention, based on the physical mixture or pulverization of the PDE 4 inhibitor, whose solubility is low, with fillers that are then granulated with aqueous PVP solutions or for which the granulated suspension of the PDE 4 inhibitor in aqueous PVP solutions is used, which is a surprise, the interaction between PVP and the PDE 4 inhibitor, whose solubility is low, is similar to that obtained in a solid solution of PVP and PDE 4 inhibitor. For obtaining the dosage form of this invention, it is also possible to issue several technical studies as variants of the production of solid solutions using the solid solvent process.

Image description

Figure 1 shows the time course of the average concentration of the active substance roflumilast after oral administration of 0.5 mg (2 tablets each containing 0.25 mg) of roflumilast from the dosage form of the present invention in comparison with a dosage form that does not contain PVP.

The production and preparation of the tablets of the present invention is described by means of the examples given below. The following examples explain the invention in more detail without limiting them.

Examples

Refutation of tablets from the invention

Example A

Weight based on a tablet containing 0.1 mg roflumilast

Production: (1) is mixed with part (3) and crumbled in a planetary mill. Crushing is carried out together with (2) and the remaining amount (3) is placed in a fluidized bed granulation system and 5% granulation solution (4) in distilled water is sprayed and dried under suitable conditions. (5) is added to the granules and the resulting mixture, after mixing, is pressed in a tablet press into tablets with an average weight of 65.1 mg.

Example B

Weight based on a tablet containing 0.125 mg roflumilast

Production: (1) is mixed with part (3) and crumbled in a planetary mill. Crushing is carried out together with (2) and the remaining amount (3) is placed in a fluidized bed granulation system and 5% granulation solution (4) in distilled water is sprayed and dried under suitable conditions. (5) is added to the granules and the resulting mixture, after mixing, is pressed in a tablet press into tablets having an average weight of 65.125 mg.

Example C

Weight based on a tablet containing 0.25 mg roflumilast

Production: (1) is mixed with part (3) and crumbled in a planetary mill. Crushing is carried out together with (2) and the remaining amount (3) is placed in a fluidized bed granulation system and 5% granulation solution (4) in distilled water is sprayed and dried under suitable conditions. (5) is added to the granules and the resulting mixture, after mixing, is pressed in a tablet press into tablets with an average weight of 59.5 mg.

Example D

Weight based on a tablet containing 0.25 mg roflumilast

Production: (1) is mixed with part (3) and crumbled in a planetary mill. Crushing is carried out together with (2) and the remaining amount (3) is placed in a fluidized bed granulation system and 5% granulation solution (4) in distilled water is sprayed and dried under suitable conditions. (5) is added to the granules and the resulting mixture, after mixing, is pressed in a tablet press into tablets with an average weight of 65.25 mg.

Example E

Weight based on a tablet containing 0.5 mg roflumilast

Production: (1) is mixed with part (3) and crumbled in a planetary mill. Crushing is carried out together with (2) and the remaining amount (3) is placed in a fluidized bed granulation system and 5% granulation solution (4) in distilled water is sprayed and dried under suitable conditions. (5) is added to the granules and the resulting mixture, after mixing, is pressed in a tablet press into tablets having an average weight of 65,500 mg.

Example F

Weight based on a tablet containing 0.5 mg roflumilast

Production: (1) is mixed with part (3) and crumbled in a planetary mill. Crushing is carried out together with (2) and the remaining amount (3) is placed in a fluidized bed granulation system and 5% granulation solution (4) in distilled water is sprayed and dried under suitable conditions. (5) is added to the granules and after mixing, the resulting mixture is pressed in a tablet press into tablets with an average weight of 130.5 mg.

Example G

Weight based on a tablet containing 2.5 mg roflumilast

Production: (1) is mixed with part (3) and crumbled in a planetary mill. Crushing is carried out together with (2) and the remaining amount (3) is placed in a fluidized bed granulation system and 5% granulation solution (4) in distilled water is sprayed and dried under suitable conditions. (5) is added to the granules and the resulting mixture, after mixing, is pressed in a tablet press into tablets with an average weight of 61.75 mg.

Example H

Production of tablets containing 0.1 mg of roflumilast as an active ingredient

(weight for a batch of 70,000 tablets)

Production: (1) is mixed with 70 g (3) and crumbled in a planetary mill. Crushing is carried out together with (2) and the remaining amount (3) is placed in a fluidized bed granulation system and 5% of the granulation solution (4) in distilled water is sprayed. (Joining pressure: 3 bar; production temperature: 28-33 °C; air flow ratio in the first third of the spraying process: 100 m<3>/h; air flow ratio after that during spraying: 150 m /h; inlet air temperature: 40-70 °C; spraying speed: 30-40 g/min). After finishing spraying, drying is carried out until the temperature of the product rises to 34 °C. The granules are passed through a steel sieve with an opening size of 0.8 mm and the relative surface humidity is measured and adjusted to a value in the range of 20-50%. (5) is added to the granules and the resulting mixture, after mixing, is pressed in a tablet press into tablets with an average weight of 65.1 mg.

Example 1

Production of tablets containing 0.25 mg of roflumilast as an active ingredient

(weight of a batch of 70,000 tablets)

Production: 19.25 g (1) is mixed with 192.5 g (3) and ground in a planetary mill. Crushing is carried out together with (2) and the remaining amount (3) is placed in a fluidized bed granulation system and 5% of the granulation solution (4) in distilled water is sprayed.

(Joining pressure: 3 bar; production temperature: 28-33 °C; air flow ratio in the first third of the spraying process: 100 m<3>/h; air flow ratio after that during spraying: 150 m<3>/h; inlet air temperature: 40-70 °C; spraying speed: 30-40 g/min). After finishing spraying, drying is carried out until the temperature of the product rises to 34 °C. The granules are passed through a steel sieve with an opening size of 0.8 mm and the relative surface humidity is measured and adjusted to a value in the range of 20-50%. (5) is added to the granules and the resulting mixture is pressed after mixing

tablet press into tablets having an average weight of 65.5 mg.

Example J

Production of tablets containing 0.1 mg of roflumilast as an active ingredient

(weight for a batch of 70,000 tablets)

Production: (1) is homogeneously suspended in a granular solution with (4) in purified water. (2) is placed in a fluidized bed granulation system and granulated with the granulation slurry described above and then dried. (5) sc is added to the granules and the resulting mixture, after mixing, is pressed in a tablet press into tablets with an average weight of 65.1 mg.

Example K

Production of tablets containing 0.25 mg of roflumilast as an active ingredient

(weight for a batch of 70,000 tablets)

Production: (1) is homogeneously suspended in a granular solution with (4) in purified water. (2) is placed in a fluidized bed granulation system and granulated with the granulation slurry described above and then dried. (5) is added to the granules and the resulting mixture, after mixing, is pressed in a tablet press into tablets with an average weight of 62.25 mg.

Example L

Weight based on a tablet containing 0.25 mg roflumilast

Production: The dispersion is obtained from (4) and water and (1) is homogeneously suspended in it. (5) is dissolved in water and added to the dispersion. (2) and (3) are granulated in a suitable fluidized bed granulation system with dispersion under suitable conditions. (6) is added to this mixture and the resulting mixture after mixing is pressed into

tablet press into tablets having an average weight of 65,650 mg.

Example M

Weight based on a tablet containing 0.25 mg roflumilast

Production: (1) is mixed with part (3) and crumbled in a planetary mill. Crushing is carried out together with (2) and the remaining amount of (3) is placed in a fluidized bed granulation system and 5% granulation solution of (4) and (5) in distilled water is sprayed and dried under suitable conditions. (6) is added to the granules and the resulting mixture, after mixing, is pressed in a tablet press into tablets with an average weight of 66.55 mg.

Example Ml

Formulation for pediatric use

Weight based on a tablet containing 0.125 mg roflumilast

The formulation is produced according to the procedure described above.

Physical tests and comparative tests with non-PVP dosage forms

used as a binder

ExampleN

The time of decomposition and release of the active ingredient was determined for the corresponding dosage form from example D.

Disintegration time: disintegration time was determined using a disintegration tester using the method described in the European Pharmacopoeia.

Result: 7.08 minutes.

Active ingredient release: Active ingredient release was determined as described in the US Pharmacopoeia (USP XXV; ed. 2).

Result: 78% of the active ingredient is released after 15 minutes, and quantitative release was noted after 60 minutes.

Example O

Production of a dosage form containing roflumilast in which no PVP was used:

Weight based on a tablet containing 0.25 mg roflumilast

Production: The dispersion is obtained from (4) and water and (1) is homogeneously suspended in it. (2) and (3) are granulated in a suitable fluidized bed granulation system with dispersion under suitable conditions. (5) is added to the dry granules and a homogenized mixture is obtained. (5) is added to this mixture and the resulting mixture after mixing is compressed in a tablet press into tablets having an average weight of 96.438 mg.

Internal study

Plan: 24 trials, 3 transition periods, randomization; dose in each case 0.5 mg (2 tablets each containing 0.25 mg roflumilast). The concentration of the active substance roflumilast after oral administration of 0.5 mg (2 tablets each containing 0.25 mg) of roflumilast was investigated for the following dosage forms:

With PVP as a binder:

The tablet that corresponds to the procedure of obtaining from example D, is marked as "treatment A" and thus shown in the following text. The tablet that corresponds to the procedure of obtaining from example K, is marked as "treatment B" and thus shown in the following text.

Without PVP as a binder:

The tablet that corresponds to the procedure of obtaining from example O, is marked as "treatment C" and thus shown in the following text.

The results are shown in Figure 1. Higher levels of the active substance were obtained significantly faster after oral administration of the dosage form with PVP as a filler compared to the dosage form without PVP. The rate of absorption is readily apparent to increase with the dosage form of the present invention.

Industrial applicability

The dosage forms of the present invention can be used for the treatment and prevention of all diseases related to the treatment or prevention of diseases with the use of PDE 4 inhibitors. Selective cyclic nucleotide phosphodiesterase (PDE) inhibitors (especially type 4) are suitable, on the one hand, as bronchial therapeutic agents (for the treatment of respiratory diseases caused by obstruction due to their dispersed effects, but also due to their effect of increasing the rate of breathing and respiratory action) and to eliminate the swelling of breathing dysfunctions due to the vasodilation effect, but also on the other hand, especially for the treatment of diseases, especially of an inflammatory nature, for example, breathing (asthmatic prophylaxis), skin, central nervous system, intestines, eyes and joints, which are supported with mediators such as histamine, PAF (platelet activating factor), arachoid acid derivatives, such as leukotrienes and prostaglandin, cytokines, interleukins, chemokines, alpha-, beta- and gamma-interferons, tumor necrosis factors (TNF) or free oxygen radicals and proteases. The pharmaceutical composition of this invention can thus be used in human and veterinary medicine, for example, for the treatment and prophylaxis of the following diseases: acute and chronic (especially inflammatory and allergic-induced) respiratory diseases of various etiologies (bronchitis, allergic bronchitis, bronchial asthma, COPD); dermatoses (especially proliferative, inflammatory and allergic nature) such as, for example, psoriasis (vulgaris), toxic and allergic contact eczema, atypical eczema, seborrheic eczema, lichen eczema, sunburn, pruritus in the genital-anal region, baldness, hypertrophic scars, discoid lupus erytodermatosis, follicular and extensive pyodermatitis, endogenous and exogenous acne, acne rocasea and others reproduction, inflammation and allergic skin diseases; diseases based on the excessive release of TNF from leukotrienase, for example, diseases of the arthritic type (rheumatoid arthritis, rheumatic spondylosis, osteoporosis and other arthritic conditions), diseases of the immune system (AIDS, multiple sclerosis), types of shock (septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome and ARDS (respiratory distress syndrome in adults) and inflammation in the gastro-intestinal area in general (Cronch's disease and ulcerative colitis); diseases based on allergic and/or chronic abnormal immunotoxic reactions in the area of the upper respiratory tract (pharynx, nose) and adjacent areas (nasal sinuses, eyes), such as, for example, allergic rhinitis/sinusitis, allergic conjunctivitis and nasal polyps; but also heart diseases that can be treated with PDE inhibitors, such as, for example, heart failure or diseases that can be treated due to of the tissue-relaxing effect of PDE inhibitors, as which are, for example, increased dysfunction or carts in the kidneys and urinary channels with kidney stones; or further CNS diseases such as, for example, depression or arteriosclerotic dementia.

The dosage form in the present invention includes a PDE 4 inhibitor in a dose customary for the treatment of certain diseases. The dose of the active ingredient is in the amount usual for PDE 4 inhibitors and it is possible to give a daily dose in one or more dosage units. The normal dose in systematic therapy (oral) is between 0.001 mg and 3 mg per kilogram per day. A dosage form which is preferred according to the present invention contains from 0.01 mg to 5 mg of roflumilast, preferably from 0.05 mg to 2.5 mg, particularly preferably from 0.1 mg to 0.5 mg of roflumilast per dosage unit. Examples of the pharmaceutical preparation in this invention contain 0.1 mg, 0.125 mg, 0.25 mg and 0.5 mg of roflumilast per dosage unit. Normally, one or more dosage units of the present invention are taken once daily. If desired, it is also possible for one or more dosage units of this invention to be taken more than once a day.

Claims (47)

1. An oral dosage form in the form of a tablet, characterized in that it contains a PDE 4 inhibitor together with polyvinylpyrilidone, and one or more suitable pharmaceutical excipients, wherein the PDE 4 inhibitor is a compound selected from the group of compounds of formula I in which R1 is difluoromethoxy, R 2 is cyclopropylmethoxy, and R3 is 3,5-dichloropyrid-4-yl, as well as salts of this compound, and N-oxide of pyridine and its salts, and where the dosage form does not contain a PDE 4 inhibitor uniformly dispersed or dissolved in an excipient matrix composed of one or more excipients selected from the group of fatty alcohols, triglycerides, partial glycerides and fatty acid esters. 2. Dosage form according to claim 1, characterized in that the PDE 4 inhibitor is N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide (roflumilast). 3. Dosage form according to claim 1, characterized in that the PDE 4 inhibitor is N-oxide pyridine of the compound of formula I. 4. Dosage form according to claim 2, characterized in that it contains from 0.01 mg to 5 mg roflumilast, 0.05 mg to 2.5 mg roflumilast or 0.1 mg to 0.5 mg roflumilast per unit dose. 5. Dosage form according to claim 4, characterized in that it contains 0.5 mg of roflumilast per dose unit. 6. Dosage form according to claim 1, characterized in that the presence of polyvinylpyrrolidone is from 1 to 5% by weight. 7. Dosage form according to claim 1, characterized in that the presence of polyvinylpyrrolidone is from 2 to 3% by weight. 8. Dosage form according to claim 1, characterized in that the polyvinylpyrrolidone is selected from the group consisting of Kolidon 25 with a molecular weight of 28,000 - 34,000, Kolidon 30 with a molecular weight of 44,000 - 54,000 and Kolidon 90 F with a molecular weight of 1,000,000 - 1,500,000. 9. Dosage form according to claim 1, characterized in that the excipients are from the group of fillers, binding substances, tablet disintegrators, lubricants or releasing agents, flavoring substances, buffer substances, preservatives, coloring substances and emulsifiers. 10. Dosage form according to claim 1, characterized in that the PDE 4 inhibitor content is up to 20% by weight. 11. Dosage form according to claim 9, indicated by the fact that it is a tablet and where the filler content is from 40 to 99% by weight. 12. Dosage form according to claim 9, characterized in that the filler is selected from the group of calcium carbonate, sodium carbonate, sugar alcohols such as mannitol, sorbitol, xylitol or maltitol, starches such as corn starch, potato starch and wheat starch, microcrystalline cellulose, saccharides such as glucose, lactose, lactose monohydrate, levulose, sucrose, dextrose and their mixtures. 13. Dosage form according to claim 12, characterized in that the filler is selected from the group of corn starch, microcrystalline cellulose, lactose and their mixture. 14. Dosage form according to claim 9, characterized in that the lubricant or release agent is selected from the group of sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid, talc and colloidal anhydrous silica. 15. Dosage form according to claim 1, characterized in that it is a tablet. 16. Dosage form according to claim 15, characterized in that the pharmaceutical excipients are at least one filler and at least one lubricant or release agent. 17. Dosage form according to claim 15, characterized in that it contains 18. Dosage form according to claim 15, characterized in that it contains 19. Dosage form according to claim 15, characterized in that it contains 20. Dosage form according to claim 1, characterized in that it contains a solid solution of a PDE 4 inhibitor in PVP as a carrier. 21. The dosage form according to claim 20, characterized in that it is a solid solution with an amorphous structure, in which the PDE 4 inhibitor is in the form of a molecular dispersion in the carrier material. 22. The method for obtaining a dosage form according to claim 1, characterized in that it contains the steps of: (a) obtaining a mixture of PDE 4 inhibitors of formula I according to claim 1 and pharmaceutical excipients and (b) granulation of the mixture obtained in (a) with an aqueous solution of polyvinylpyrrolidone. 23. The method according to claim 22, characterized in that it includes drying the granules and additional mixing of other pharmaceutical excipients, mixing with a releasing agent and pressing on a tablet press. 24. The method according to claim 22, characterized in that it includes the method of wetting the preparations obtained after granulation into granules. 25. The method according to claim 22, characterized in that the granulation takes place in a fluidized bed granulator under suitable conditions. 26. The method according to claim 22, characterized in that in step (a) the PDE 4 inhibitor is additionally mixed with other excipients in the form of grinding with a pharmaceutical excipient. 27. The method according to claim 26, characterized in that the pharmaceutical excipient is a filler. 28. The method according to claim 22, characterized in that it includes granulation of a mixture of (a) PDE 4 inhibitor of formula I according to claim 1, or grinding of PDE 4 inhibitor of formula I according to claim 1 with corn starch, (b) corn starch and (c) lactose monohydrate with an aqueous solution of polyvinylpyrrolidone, drying the granules, mixing the granules with release agents and pressing on a tablet press. 29. The method according to claim 22, characterized in that it contains granulation of a mixture of (a) PDE 4 inhibitors of formula I according to claim 1, or grinding of PDE 4 inhibitors of formula I according to claim 1 with corn starch, (b) corn starch, (c) microcrystalline cellulose and (d) sodium carboxymethyl starch with an aqueous solution of polyvinylpyrrolidone, drying the granules, mixing the granules with a release agent and pressing on a tablet press 30. The method of obtaining a dosage form according to claim 1, characterized in that it contains steps: (a) obtaining a mixture of pharmaceutical excipients, (b) granulation of the mixture obtained in (a) with a suspension of the PDE 4 inhibitor of formula I according to claim 1 in an aqueous solution of PVP. 31. The method according to claim 30, characterized in that it includes granulation of a mixture of corn starch and lactose monohydrate with a suspension of PDE 4 inhibitor of formula I according to claim 1 in an aqueous solution of PVP, drying the granules, mixing the granules with a release agent and pressing on a tablet press. 32. The method for obtaining a dosage form according to claim 1, characterized in that it includes the production of a solid solution of polyvinylpyrrolidone and PDE 4 inhibitor of formula I according to claim 1. 33. The method according to claim 32, characterized in that it is a solid solution with an amorphous structure in which the PDE 4 inhibitor of formula I according to claim 1 is in the form of a molecular dispersion in polyvinylpyrrolidone. 34. The method according to claim 32, indicated by the fact that the solid solution is obtained by a dissolution process in which polyvinylpyrrolidone, PDE 4 inhibitor and appropriate other pharmaceutical excipients are dissolved in a suitable solvent, then the solvent is removed again by spray drying, normal drying, vacuum drying or freeze drying. 35. The method according to claim 32, characterized in that the solid solution is produced by a mixing process where the PDE 4 inhibitor and other pharmaceutical excipients are vigorously mixed together with the polyvinylpyrrolidone. 36. The method for obtaining the dosage form according to claim 1, indicated by the fact that it includes the steps: (a) obtaining the preparation of the active ingredient in the form of a solid solution in polyvinylpyrrolidone of the PDE 4 inhibitor of formula I according to claim 1, (b) obtaining the mixture of the preparation of the active ingredient and pharmaceutical excipients and (c) granulating the mixture obtained in (b) with an aqueous solution of polyvinylpyrrolidone. 37. The method according to claim 36, for obtaining a dosage form in the form of a tablet, characterized in that the granules obtained in step (c) are dried, mixed with lubricants and release agents and pressed on a tablet press. 38. The method according to claim 36, for obtaining a dosage form in the form of granules, characterized in that the wet granules obtained in step (c) are processed using the extruder/spheronization process into suitable granules. 39. Method for obtaining the dosage form according to claim 1 in the form of granules, characterized in that dispersions/suspensions of active ingredient preparations are applied in the form of a solid solution in polyvinylpyrrolidone of the PDE 4 inhibitor in a suitable solvent on carriers in the form of granules. 40. The method according to claim 39, characterized in that the carriers are in the form of granules or granules containing HPMC. 41. Application of the compound of formula I according to claim 1, characterized in that in the production of a dosage form for the treatment or prophylaxis of diseases using a PDE 4 inhibitor. 42. Application according to claim 41, characterized in that the disease is selected from the group of asthma or airway obstruction. 43. Application according to claim 42, characterized in that the disease is COPD (chronic obstructive pulmonary disease). 44. Application according to claim 41, characterized in that the disease is selected from the group of acute and chronic respiratory diseases. 45. Application according to claim 44, characterized in that the disease is selected from bronchitis and allergic bronchitis. 46. Application according to one of claims 42 to 45, characterized in that the PDE 4 inhibitor is N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide (roflumilast). 47. Application according to claim 46, characterized in that the dosage form contains 0.5 mg of roflumilast.